Chemoimmunotherapy Shakes Up Metastatic and Early-Stage TNBC

Chemoimmunotherapy combinations have transformed the treatment landscape for patients with triple-negative breast cancer, but balancing potential efficacy with the risk of toxicity with these regimens is critical in both the metastatic and early-stage settings.

Chemoimmunotherapy combinations have transformed the treatment landscape for patients with triple-negative breast cancer (TNBC), but balancing potential efficacy with the risk of toxicity with these regimens is critical in both the metastatic and early-stage settings, said Hope S. Rugo, MD, during the Giants of Cancer Care® lecture at the 20th Annual International Congress on the Future of Breast Cancer® East meeting, a program hosted by the Physicians’ Education Resource® (PER®), LLC.1

TNBC, which has a higher tumor mutational burden vs HER2-positive and hormone receptor (HR)–positive breast cancer, was the first breast cancer subtype in which immunotherapy was evaluated, explained Rugo, a professor of medicine in the Department of Medicine (Hematology/Oncology) and the director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

Although responses to single-agent checkpoint inhibitors were modest, they paved the way to evaluate immune-based combinations in the first-line setting for patients with metastatic TNBC, as well as in the early-stage setting to optimize treatment.

Treatment with chemotherapy induces changes in the immune microenvironment, said Rugo, who is also the 2020 Giants of Cancer Care® award winner in Education. This concept provided the clinical rationale to evaluate checkpoint inhibitors in combination with chemotherapy in TNBC, Rugo said.

Findings from the phase 3 IMpassion130 trial (NCT02425891) led to the first FDA approval of a checkpoint inhibitor, atezolizumab (Tecentriq), in combination with chemotherapy, nab-paclitaxel (Abraxane), for the treatment of patients with unresectable locally advanced or metastatic TNBC whose tumors are PD-L1 positive.2

The data from the final analysis of IMpassion130 demonstrated that, at a median follow-up of 18.8 months, the median overall survival (OS) was 25.4 months with atezolizumab/nab-paclitaxel vs 17.9 months with placebo/nab-paclitaxel in patients with PD-L1–positive TNBC (HR, 0.67; 95% CI, 0.53-0.86).3 The 3-year OS rates were 36% vs 22%, respectively.

“Sometimes [we] worry that over time [we] are going to see a narrowing of OS, but the OS difference [demonstrated in the final analysis of IMpassion130] is 7.5 months, so it broadened over time and was very confirmatory,” Rugo said.

Another checkpoint inhibitor, pembrolizumab (Keytruda), demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when combined with chemotherapy in patients with previously untreated, locally recurrent, inoperable or metastatic TNBC whose tumors expressed PD-L1 (combined positive score [CPS] of 10 or higher) in the phase 3 KEYNOTE-355 trial (NCT02819518).4 In this PD-L1–enriched population, the median PFS was 9.7 months with pembrolizumab/chemotherapy vs 5.6 months with placebo/chemotherapy (HR, 0.65; P = .0012). No statistically significant difference in PFS was observed with the addition of pembrolizumab in patients with a PD-L1 CPS of 1 or higher (HR, 0.74; P = .0014).

On November 13, 2020, the FDA granted an accelerated approval to pembrolizumab plus chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).5 

Although responses with immunotherapy are good in TNBC, safety remains a consideration, said Rugo. Immune-related adverse effects (irAEs), including rash, thyroid changes, hepatitis, and adrenal insufficiencies, remain in need of careful management.6

“[Managing irAEs] can be quite difficult,” said Rugo. “In patients who need chemotherapy and have visceral disease, if [we] need to hold or stop therapy for grade 4 hepatitis, that is a big issue. We all need to be very educated in recognizing these events.”

In light of the IMpassion130 and KEYNOTE-355 trials, the role of checkpoint inhibitors was complicated with the negative results of the phase 3 IMpassion131 trial (NCT03125902). The combination of first-line atezolizumab and paclitaxel failed to improve PFS or OS compared with placebo and paclitaxel in patients with unresectable locally advanced or metastatic TNBC.7

“We have absolutely no idea why this trial was negative, but it leads us to conclude that nab-paclitaxel [should] be our chosen chemotherapy partner rather than paclitaxel. The balance of evidence [with IMpassion130, KEYNOTE-355, and IMpassion131] suggests that checkpoint inhibitors [provide] benefit to [patients with] PD-L1–positive metastatic TNBC,” commented Rugo.

Notably, trials are ongoing in the metastatic setting to try to improve upon responses demonstrated with chemotherapy. Alternative partners for checkpoint inhibitors, such as fam-trastuzumab deruxtecan-nxki (Enhertu) in the phase 1b/2 BEGONIA trial (NCT03742102), binimetinib (Mektovi), sacituzumab govitecan-hziy (Trodelvy), or liposomal doxorubicin in the phase 2 InCITe trial (NCT03971409), and olaparib (Lynparza) in the phase 2/3 KEYLYNK-009 trial (NCT04191135), are being evaluated.8-10

Checkpoint Inhibitors Elicit Efficacy Irrespective of PD-L1 Status in Early-Stage TNBC

As part of the ongoing, phase 2 I-SPY2 trial (NCT01042379), pembrolizumab in combination with neoadjuvant chemotherapy led to a more than doubling in estimated pathologic complete response (pCR) rates vs neoadjuvant chemotherapy alone in patients with early-stage, high-risk ERBB2-negative breast cancers, including TNBC.11

Also in the neoadjuvant setting, the phase 3 IMpassion031 trial (NCT03197935) demonstrated that atezolizumab plus nab-paclitaxel and anthracycline-based treatment significant improved pCR rates in patients with early-stage TNBC.12 The pCR rates were 58% with the atezolizumab-containing regimen vs 41% with the placebo-containing regimen (rate difference, 17%; 95% CI, 6%-27%; one-sided P = .0044).

Rugo also highlighted the phase 3 KEYNOTE-522 trial (NCT03036488). Initial findings from the study demonstrated a 64.8% pCR rate with neoadjuvant pembrolizumab plus paclitaxel and carboplatin followed by adjuvant pembrolizumab vs 51.2% with placebo plus paclitaxel and carboplatin followed by placebo (estimated treatment difference, 13.6%; 95% CI, 5.4%-21.8%; P < .001).13

Notably, unlike in the metastatic setting, responses in both IMpassion031 and KEYNOTE-522 were observed irrespective of PD-L1 status. However, the irAEs observed in the metastatic setting were present in the early-stage setting, Rugo explained.

In a briefing document that was released ahead of a hearing from the FDA’s Oncologic Drugs Advisory Committee (ODAC), the study investigators attributed 1 death from pneumonitis that occurred on the KEYNOTE-522 trial to neoadjuvant pembrolizumab treatment.14 In the adjuvant setting, the investigators noted 2 pembrolizumab-related deaths from a pulmonary embolism and autoimmune encephalitis.

The committee indicated that event-free survival (EFS) results from KEYNOTE-522 were needed, Rugo explained. Therefore, on February 9, 2021, ODAC unanimously voted 10 to 0 against the approval of pembrolizumab in combination with chemotherapy as neoadjuvant treatment for patients with high-risk, early-stage TNBC.15 The vote deferred regulatory action on the submitted biologics license application for the regimen.

Results of the EFS analysis, which were presented during an ESMO Virtual Plenary session on July 15, 2021, demonstrated an EFS rate of 84.5% with the pembrolizumab-containing regimen vs 76.8% with the placebo-containing regimen (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).16 This translated to a 7.7% improvement in EFS with the addition of pembrolizumab. Notably, all patient subgroups favored the addition of pembrolizumab, irrespective of nodal status, tumor size, carboplatin schedule, PD-L1 status, age, and ECOG performance status.

Additional findings showed that the EFS rates in patients who achieved a pCR were 94.4% with pembrolizumab vs 92.5% with placebo. In patients who did not achieve a pCR, the EFS rates were 67.4% vs 56.8%, respectively. Additionally, the rates of distant recurrence-free survival were 87.0% vs 80.7%, respectively (HR, 0.61; 95% CI, 0.46-0.82). The OS rates were 89.7% vs 86.9%, respectively (HR, 0.72; 95% CI, 0.51-1.02; P = .03214).


Ongoing research efforts are fleshing out whether treatment de-escalation with neoadjuvant chemoimmunotherapy regimens is feasible, Rugo said.

“This represents a new standard of care for early-stage TNBC, but we need to balance cost and toxicity in high-risk disease. Since these data are new, we have to start on [this] approach now,” concluded Rugo.

References

  1. Rugo HS. Deploying checkpoint inhibitors in TNBC. Presented at: 20th Annual International Congress on the Future of Breast Cancer® East; July 16-17, 2021; virtual.
  2. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. News release. FDA. March 8, 2019. Accessed July 16, 2021. https://bit.ly/370skLR.
  3. Iwata H, Emens L, Adams S, et al. IMpassion130: final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Ann Oncol. 2020;31(suppl 6):S1261-S1262. doi:10.1016/j.annonc.2020.10.069
  4. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9
  5. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. November 13, 2020. Accessed July 16, 2021. https://bit.ly/3hK2dij.
  6. D’Abreo N, Adams S. Immune-checkpoint inhibition for metastatic triple-negative breast cancer: safety first? Nat Rev Clin Oncol. 2019;16(7):399-400. doi:10.1038/s41571-019-0216-2
  7. Miles D, Gligorov J, Andre F, et al. [CS30] Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi:10.1016/j.annonc.2021.05.801
  8. A study of novel anti-cancer agents in patients with metastatic triple negative breast cancer (BEGONIA). ClinicalTrials.gov. Updated June 28, 2021. Accessed July 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03742102.
  9. Avelumab with binimetinib, sacituzumab govitecan, or liposomal doxorubicin in treating patients with stage IV or unresectable, recurrent triple negative breast cancer (InCITe). ClinicalTrials.gov. Updated July 15, 2021. Accessed July 16, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03971409.
  10. Study of olaparib plus pembrolizumab versus chemotherapy plus pembrolizumab after induction with first-line chemotherapy plus pembrolizumab in triple negative breast cancer (TNBC) (MK-7339-009/KEYLYNK-009). ClinicalTrials.gov. Updated July 15, 2021. Accessed July 16, 2021. https://clinicaltrials.gov/ct2/show/NCT04191135.
  11. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650
  12. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X
  13. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
  14. Pembrolizumab Oncologic Drugs Advisory Committee briefing document. FDA. Published February 9, 2021. Accessed July 16, 2021. https://www.fda.gov/media/145654/download.
  15. Final summary minutes of the Oncologic Drugs Advisory Committee Meeting. FDA. February 9, 2021. Accessed July 16, 2021. https://www.fda.gov/media/147887/download.
  16. Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC. Presented at: ESMO Virtual Plenary; July 15-16, 2021. VP7-2021. doi:10.1016/j.annonc.2021.06.014